Effect of the V3 Loop Deletion of Envelope Glycoprotein on Cellular Responses and Protection against Challenge with Recombinant Vaccinia Virus Expressing gp160 of Primary Human Immunodeficiency Virus Type 1 Isolates

Abstract

The magnitude and breadth of cytotoxic-T-lymphocyte (CTL) responses induced by human immunodeficiency virus type 1 (HIV-1) envelope protein from which the hypervariable V3 loop had been deleted (ΔV3) were evaluated in the HLA-A2/K^btransgenic mice. It was demonstrated that vaccines expressing the ΔV3 mutant of either HIV-1_IIIBor HIV-1_89.6envelope glycoprotein induced broader CD8⁺T-cell activities than those elicited by the wild-type (WT) counterparts. Specifically, the differences were associated with higher responses to conserved HLA-A2-restricted CTL epitopes of the envelope glycoprotein and could be correlated with an increased cell surface occupancy by the epitope-HLA-A2 complexes in target cells expressing the ΔV3 mutant. Using recombinant vaccinia virus expressing heterologous gp160 of primary HIV-1 isolates in a murine challenge system, we observed that the extent of resistance to viral transmission was higher in animals immunized with the ΔV3 than the WT envelope vaccine. The protection was linked to the presence of envelope-specific CD8⁺T cells, since depletion of these cells by anti-CD8 antibody treatment at the time of challenge abolished the vaccine-induced protection. The results from our studies provide insights into approaches for boosting the breadth of envelope-specific CTL responses.